Iron-containing nanoparticles (e.g., iron oxide nanoparticles or “iron oxide NPs” or “IONPs”) may be used in a wide variety of applications including, but not limited to, many different medical applications.
Some methods of making iron-containing nanoparticles may include drawbacks, such as the use of toxic components that may not be suitable for one or more medical applications, the use of high reaction temperatures that may limit the choice of nanoparticle capping agents, and/or other drawbacks. Some methods may also include fractionation processes to separate the nanoparticles according to particle size.
IONPs may be prepared by a variety of methods. There are various methods of making IONPs such as co-precipitation, nonaqueous and aqueous sol-gel (Bilecka et al., “One-minute synthesis of crystalline binary and ternary metal oxide nanoparticles,” Chem. Commun., 2008, 886), microemulsion, hydrothermal/solvothermal (Sun et al., “Monodisperse MFe2O4 (M=Fe, Co, Mn) Nanoparticles,” J. Am. Chem. Soc., 2004, 126, 273-279), and sonochemical processes (Kim et al., “Synthesis of ferrofluid with magnetic nanoparticles by sonochemical method for MRI contrast agent,” J. Magn. Magn. Mater., 2005, 289, 328), which have been used with acceptable results. Among the aqueous phase syntheses, Massart's method of co-precipitation has been used for its simplicity and the final product is often comprised of both magnetite (Fe3O4) and maghemite (γ-Fe2O3). (Massart, “Preparation of aqueous magnetic liquids in alkaline and acidic media,” IEEE Trans. Magn., 1981,)7, 1247-1248.) In short, ferric and ferrous salts in a 2 to 1 ratio dissolved in deionised (DI) and deoxygenated water are precipitated as IONPs, by carefully adjusting the pH of the reaction mixture to 11 or above using a base, usually aqueous ammonia (NH3.H2O) or sodium hydroxide (NaOH). (Kang et al., “Synthesis and Characterization of Nanometer-Size Fe3O4 and γ-Fe2O3 Particles,” Chem. Mater., 1996, 8, 2209-2211.) Massart's method is a mild way of preparing bare IONPs and IONPs with hydrophilic coatings by a one-pot synthesis. Parameters including temperature and the ratio of iron salts control the final product formation. The pH has to be carefully monitored at each step from synthesis to purification of the final product. However, the final nanoparticle product usually consists of two phases, magnetite (Fe3O4) and maghemite (γ-Fe2O3). The draw-back with this aqueous phase synthesis is that variations in the molar ratio of the iron salts often result in complex changes to the crystal structure of the final IONPs and the final product is often a mixture of magnetite and maghemite (Massart, “Preparation of aqueous magnetic liquids in alkaline and acidic media,” IEEE Trans. Magn., 1981, 17, 1247-1248.). Also the procedure has difficulties in achieving IONPs with narrow size distributions.
To overcome these setbacks, a number of high-temperature syntheses were developed that follow a thermal decomposition of iron species such as iron(III)acetylacetonate, Fe(acac)3, and iron pentacarbonyl, Fe(CO)5, in an organic phase (or solvent). (Hyeon et al., “Synthesis of Highly Crystalline and Monodisperse Maghemite Nanocrystallites without a Size-Selection Process,” J. Am. Chem. Soc., 2001, 123, 12798-12801.)
Sun et al. reported an organic phase synthesis of monodisperse magnetite nanoparticles starting from Fe(acac)3. (Sun et al., “Size-Controlled Synthesis of Magnetite Nanoparticles,” J. Am. Chem. Soc., 2002, 124, 8204-8205.) The precursor Fe(acac)3 in phenyl ether, in the presence of 1,2-hexanediol, oleic acid, and oleyl amine was refluxed at 265° C. to yield magnetite nanoparticles that are 4 nm in diameter. (Sun et al., “Size-Controlled Synthesis of Magnetite Nanoparticles,” J. Am. Chem. Soc., 2002, 124, 8204-8205.) Larger IONPs of 8, 12 and 16 nm were synthesized starting from these 4 nm particles in the presence of varying concentration of the precursor Fe(acac)3, via a seed-mediated growth procedure. (Sun et al., “Size-Controlled Synthesis of Magnetite Nanoparticles,” J. Am. Chem. Soc., 2002, 124, 8204-8205.)
Pinna et al. disclosed a high-temperature synthesis of magnetite nanoparticles from Fe(acac)3 in the absence of a specific surfactant molecules, where benzyl alcohol serves both as solvent and protective ligand. (Pinna et al., “Magnetite Nanocrystals: Nonaqueous Synthesis, Characterization, and Solubility,” Chem. Mater., 2005, 17, 3044-3049.) The precursor is thermally decomposed at 200° C. to yield magnetite particles with an average diameter of 20 to 25 nm. (Pinna et al., “Magnetite Nanocrystals: Nonaqueous Synthesis, Characterization, and Solubility,” Chem. Mater., 2005, 17, 3044-3049.)
Other strategies may include a sol-gel process that may require high temperatures and bulky hydrophobic organic surfactant molecules to yield monodisperse IONPs. In a sol-gel method using high temperatures, 15-nm Fe3O4 particles were made from a metal alkoxide (Fe(O-tBu)2(THF)2) at 300° C. (Gun'ko et al., “Magnetic nanoparticles and nanoparticle assemblies from metallorganic precursors,” J. Mater. Sci. Mater. Electron., 2001, 12(4-6), 299-302.) Others have reported yielding reasonably monodisperse IONPs, while following such high-temperature protocols. (Liu et al., “One-pot polyol synthesis of monosize PVP-coated sub-5 nm Fe3O4 nanoparticles for biomedical applications,” J. Magn. Magn. Mater., 2007, 310, e815-e817; Ge et al., “Superparamagnetic Magnetite Colloidal Nanocrystal Clusters” Angew. Chem., Int. Ed., 2007, 46, 4342-4345; Figuerola et al., “One-Pot Synthesis and Characterization of Size-Controlled Bimagnetic FePt-Iron Oxide Heterodimer Nanocrystals,” J. Am. Chem. Soc., 2008, 130, 1477-1487; Xu et al., “Synthesis of Magnetic Microspheres with Immobilized Metal Ions for Enrichment and Direct Determination of Phosphopeptides by Matrix-Assisted Laser Desorption Ionization Mass Spectrometry,” Adv. Mater. 2006, 18, 3289-3293.) The as-synthesized IONPs in high temperature organic-phase syntheses do not form colloidal solutions in aqueous and physiological media, which may render them unsuitable for many biomedical applications as such, and requires sophisticated post-preparative procedures to make them “water soluble.” (Yin et al., “The effects of particle size and surface coating on the cytotoxicity of nickel ferrite,” Biomaterials, 2005, 26, 5818-5826; Hoshino et al., “Physicochemical Properties and Cellular Toxicity of Nanocrystal Quantum Dots Depend on Their Surface Modification,” Nano Lett., 2004, 4, 2163-2169.) As a direct method, Gao et al. reported the high-temperature synthesis of 5-nm IONPs that are water soluble from Fe(acac)3 and FeCl3.6H2O by refluxing the precursors in 2-pyrrolidone which serves as solvent and ligand. (Li et al., “One-Pot Reaction to Synthesize Water-Soluble Magnetite Nanocrystals,” Chem. Mater., 2004, 16, 1391-1393; Li et al., “Preparation of Water-Soluble Magnetite Nanocrystals from Hydrated Ferric Salts in 2-Pyrrolidone: Mechanism Leading to Fe3O4,”Angew. Chem. Int. Ed., 2005, 44, 123-126.)
Inorganic NP syntheses by precipitation may involve more simple steps and may need not require high temperatures. NPs may be precipitated out starting with soluble metal cations using reducing agents (e.g., gaseous H2, solvated NaBH4, hydrazine hydrate (N2H4.H2O), or hydrazine dihydrochloride, etc.). Reduction of inorganic and organometallic precursors by sodium borohydride in metal NP synthesis has been used for gold, silver, iron (Huang et al., “Synthesis of Iron Nanoparticles via Chemical Reduction with Palladium Ion Seeds,” Langmuir, 2007, 23, 1419-1426), cobalt (Du et al., “Preparation and characterization of Co—Pt bimetallic magnetic nanoparticles,” J. Magn. Magn. Mater., 2006, 299, 21-28), and other multi-component NPs. (Zeng et al., “Syntheses, Properties, and Potential Applications of Multicomponent Magnetic Nanoparticles,” Adv. Funct. Mater., 2008, 18, 391-400; Zhang et al., “Magnetically Recyclable Fe@Pt Core—Shell Nanoparticles and Their Use as Electrocatalysts for Ammonia Borane Oxidation: The Role of Crystallinity of the Core,” J. Am. Chem. Soc., 2009, 131, 2778-2779.) There have been reports on the synthesis of IONPs using sodium borohydride as a reducing agent. For example, Kinoshita et al. described the reduction and hydrolysis of aqueous FeCl3.6H2O in the presence of gelatine using aqueous sodium borohydride in an undisclosed ratio of components. (Yonezawa et al., “Easy Preparation of Stable Iron Oxide Nanoparticles Using Gelatin as Stabilizing Molecules,” Jpn. J. Appl. Phys., 2008, 47, 1389-1392.) These reaction conditions yielded maghemite (γ-Fe2O3) NPs with apparently no effective reduction of Fe3+ to Fe2+ observed.
Improved methods of making iron-containing nanoparticles, particularly surface-modified iron-containing nanoparticles, may be useful.